Differentiation and characterization of subvisible particulates in therapeutic protein products
There is an expectation from regulatory agencies for companies to monitor and, if required, reduce the levels of sub-visible particles present in therapeutic protein from manufacture through their complete shelf life. While immunogenicity can be induced by a variety of mechanisms, contamination by non-protein material is known to be a potential cause. The presence of silicone oil in parenterals has attracted considerable interest, due to its use in syringe-based administration systems and the difficulty in distinguishing oil droplets from protein aggregates. In addition to protein aggregates, non-biological contaminants may act as nucleation points for aggregate growth. Consequently, particle sizing alone is not sufficient.
Guidance from the FDA for the biopharmaceutical industry states “Naturally sourced products should be evaluated for other components, protein and non-protein”. Resonant Mass Measurement (RMM) technology in the Archimedes system measures the buoyant mass of particles passing through a cantilever, allowing detection of particles with a density different to that of the buffer solution. Consequently, the Archimedes provides the ability to distinguish between negatively buoyant particles, such as proteins, and positively buoyant particles, such as silicone oil.
This application note provides an example of how Archimedes can be used to detect and quantify the formation of protein sub-visible particles and the introduction of silicone oil droplets, in response to shear stress.